A total of 79 hospitals enrolled 755 patients from June 2005 to December 2006.

731 patients had at least one cycle of chemotherapy

The median follow-up was 18.7 months

Demographics were well-balanced between the two arms aside from female gender representation, which was significantly higher in arm A

Median age was 62 yo (range 27-83)

Results are as follows:

Arm A

Arm B

p-value

Median PFS

10.7 months

9.6 months

0.018

Median OS

20.4 months

20.3 months

0.21

Response Rate

44%

44%

0.88

Toxicity was as follows:

Arm A

Arm B

p-value

Grade 3-4 toxicity

72%

82%

0.0013

Grade 3-4 toxicity excluding skin

72%

75%

0.37

Diarrhea

19%

26%

All grade toxicity

40%

84%

Death within 30 days of treatment

5%

5%

Death within 60 days of treatment

2.4%

1.9%

Treatment-related deaths

0..5%

1%

PFS: in arm B patients with grade III skin toxicity had a better progression free survival compared with those who had grade 0-1 toxicity (p<0.01)

K-ras expression was assessed using real-time polymerase chain reaction (PCR). There was no significant difference in K-ras expression between the two arms. Patients with mutant K-ras had a worse PFS when treated with cetuximab than those without the mutation. There was no difference in OS in mutant versus wild type K-ras patients.

Author's Conclusions

The addition of cetuximab to cap, OX and bev significantly worsened PFS but had no effect on OS.

There were higher rates of diarrhea and skin toxicity in arm B, but these toxicities were considered acceptable.

The grade of skin toxicity correlated with response to cetuximab.

Patients with K-ras mutations had a decrease in PFS when given cetuximab. Patients with wild type K-ras had the same outcome with and without cetuximab.

Clinical/Scientific Implications

The present study illustrates a problem that may continue to develop as more biological agents are used and combined with more standard chemotherapy drugs. It appears that subsets of patients may benefit while others may have a detriment in outcome from certain biological agents. As we use more biological agents concurrently, this relationship may become even more complicated. We need better biomarkers which may then allow us to improve our ability to identify patients who will benefit from a given therapy. This study shows that the combination of biological agents can worsen prognosis overall, but there may be a subset within the patient cohort who do benefit, in this case, those with a grade 3 skin reaction. The authors suggest that these patients may do better when treated with cetuximab, cap, OX and bev than those treated with cap, OX and bev alone. If we could select out these patients prior to initiating therapy, we may be able to better custom-tailor therapy for individual patients.

Clearly, better systemic therapies are needed for the treatment of ACC. However, the simultaneous development of better molecular markers which are predictors of therapeutic effect are also needed. At this point, without a better ability to predict who will respond to combination therapy with cetuximab, along with the greater toxicity seen in arm B, and the worse PFS seen in arm B, combined therapy with cap, OX, bev and cetuximab can not be recommended in ACC.